Sickle cell disease (SCD) and beta-thalassemia are mostly inherited beta-hemoglobinopathies that lead to chronic anemia. Both diseases are characterized by insufficient or defective expression of the beta chain of adult hemoglobin (Hb), leading to insufficient oxygen delivery to peripheral tissues. Inadequate oxygen levels in tissues causes the episodic vasoocclusive crises that cause ischemic pain and damage, often necessitating blood transfusions. It has been recognized for decades that a means to mitigate the pathophysiology of these diseases, and in particular SCD, is to substitute the mutant adult Hb with fetal Hb (HbF). HbF is normally not expressed during adulthood due to silencing. The ability to induce fetal hemoglobin expression during adulthood has recently been achieved by pharmacological means, and led to the approval of hydroxyurea (HU) to treat patients with SCD. Although HU is the current standard of care for SCD, it has an unclear mechanism of action, and the use of HU is hindered by dose-limiting toxicity and the fact that many SCD patients respond poorly or not at all. Furthermore, HU displays little efficacy for beta-thalassemia. Therapeutic options to treat beta-hemoglobinopathy remain a large, unmet medical need worldwide. FibroGen has proprietary libraries of prolyl hydroxylase (PH) inhibitors that activate the transcription factor hypoxia-inducible factor, which may play a role in regulating expression of the gamma-globin gene that comprises HbF. Preliminary data shows that PH inhibitors lead to increased HbF expression in vitro and are additive to the HbF-inducing effects of HU. We propose to screen our existing libraries of PH inhibitors to identify and optimize the pharmacophore associated with induction of HbF expression. The ultimate goal is to select and test lead candidates in non-human primates for induction of HbF in vivo. Ultimately, this will enable identification of an HbF-inducing compound that can be tested alone or in combination with HU to mitigate the pathophysiology associated with SCD and other beta-hemoglobinopathies.